DESCRIPTION (provided by investigator): Recent work from our research group shows that school-age children with phenylketonuria (PKU) exhibit impairments in two prefrontally-mediated cognitive abilities of crucial importance to early learning: working memory and strategic processing in long-term memory. These impairments are more evident in older than younger children, suggesting that the impairments are not stable across development but instead may emerge with age. In the proposed research, the developmental trajectory of working memory and strategic memory processing will be charted longitudinally to determine if impairments emerge in individual children. Two neuropathological mechanisms that may underlie impairments in prefrontally-mediated aspects of memory also will be examined. This research has implications for the development of rehabilitation strategies designed to improve learning and memory in children with PKU and other developmental disorders affecting prefrontal function. The aims and the methods for addressing the aims of this study are as follows: (1) To test the hypothesis that children with PKU exhibit impairments in prefrontally-mediated aspects of memory. To achieve this aim, working memory and strategic memory processing tasks will be administered to children with PKU who range from 7 to 18 years of age. Comparisons will be made with demographically matched, typically developing children. (2) To test the hypothesis that impairments in prefrontally-mediated aspects of memory emerge as children with PKU age. To achieve this aim, working memory and strategic memory processing will be evaluated on a longitudinal basis. By doing so, the developmental trajectory of prefrontally-mediated aspects of memory will be defined at the level of individual children. (3) To test the hypothesis that white matter abnormalities contribute to impairments in prefrontally-mediated aspects of memory in children with early-treated PKU. This aim will be achieved through the use of diffusion tensor imaging (DTI), a neuroimaging technique permitting refined examination of white matter integrity. Dopamine deficiency also will be examined by assessing blood phenylalanine (a dopamine precursor) levels. Findings from DTI and phenylalanine levels will be examined in relation to findings from the memory tasks. [unreadable] [unreadable]